N-acylglutamine derivatives and cosmetic compositions

ABSTRACT

The present invention relates to N-acylglutamine derivatives of formula (I): ##STR1## The N-acylglutamine derivatives are well compatible with oily bases and have good skin-moisturizing activity and hair growth-stimulative effect. These are useful as cosmetics and hair growth stimulants.

TECHNICAL FIELD

The present invention relates to N-acylglutamine derivatives and tocosmetics and hair growth stimulants containing the N-acylglutaminederivatives.

PRIOR ART

Japanese Published Unexamined Patent Application No. 20438/78 disclosescosmetics containing esters of N-acylamino acids, and Japanese PublishedUnexamined Patent Application No. 223206/91 (corresponding to U.S. Pat.No. 5,112,613) discloses cosmetics containing N-acylglutamine (NAG).

NAG is stable but is poorly compatible with oily bases, and emulsion incosmetics is often unstable to lower the viscosity of cosmeticscontaining NAG. Therefore, kinds of cosmetics containing NAG and theamounts of NAG contained in cosmetics are limited.

The object of the present invention is to provide N-acylglutaminederivatives which are more compatible with oily bases than NAG and aretherefore stable in cosmetics and hair growth stimulants to have goodskin-moisturizing activity in cosmetics and hair growth-stimulativeeffect in hair growth stimulants.

DISCLOSURE OF THE INVENTION

The present invention relates to N-acylglutamine derivatives representedby formula (I): ##STR2## wherein R¹ represents an alkyl having 12 to 22carbon atoms, an alkenyl having 12 to 22 carbon atoms, ##STR3##

wherein R³ represents an alkyl having 1 to 6 carbon atoms; and

R² represents an alkyl having 1 to 6 carbon atoms.

The present invention also relates to cosmetics and hair growthstimulants containing the N-acylglutamine derivatives.

The alkyl having 1 to 6 carbon atoms for the definitions of R² and R³ isa linear or branched alkyl including methyl, ethyl, propyl, isopropyl,butyl, t-butyl, pentyl and hexyl groups. The alkyl having 12 to 22carbon atoms for the definition of R¹ is a linear or branched alkylgroup including dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, stearyl, isostearyl, myristyl, octadecyl, nonadecyl,eicosanyl, henicosanyl and docosanyl groups. The alkenyl having 12 to 22carbon atoms is a linear or branched alkenyl group including oleyl,dodecenyl, elaidyl, linoleyl and linolenyl groups.

Compounds represented by formulae (I) , (II) , (III), . . . arehereinafter referred to as Compound (I), Compound (II), Compound (III),. . . , respectively.

Methods for producing Compounds (I) are mentioned below. ##STR4##

wherein R¹ and R² have the same meanings as defined above; and Prepresents a protective group for the amino group.

As the protective group for the amino group, t-butoxycarbonyl group,benzyloxycarbonyl group, etc. are used.

Compound (IV) may be obtained by reacting Compound (II) with 0.8 to 2equivalents of Compound (III) in a solvent in the presence of acondensing agent such as dicyclohexylcarbodiimide, at a temperature from-80° C. to 40° C. for 30 minutes to 2 days.

As the reaction solvent, tetrahydrofuran (THF), dioxane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), etc. are used.

Compound (I) may be obtained by removing the amino-protective group ofCompound (IV) in a solvent by trifluoroacetic acid (TFA), catalyticreduction, etc., followed by acylating it with an acid anhydride such asacetic anhydride, or with an acid halide such as acetyl chloride at 0°to 80° C for 30 minutes to 2 days. The abovementioned solvents may beused as the reaction solvent.

Compound (II), the starting material, may be obtained by introducing theabove-mentioned protective group into a commercially availableL-glutamine by a conventional method, or a commercial product ofCompound (II) may be used. ##STR5##

wherein R¹ and R² have the same meanings as defined above; and Xrepresents a halogen atom.

The halogen atom includes chlorine atom, iodine atom and bromine atom.

Compound (I) may be obtained by reacting an N-acylglutamine with 0.8 to2 equivalents of Compound (V) in the presence of a base such as sodiumhydride, cesium fluoride, triethanolamine and cesium carbonate, ifnecessary.

As the reaction solvent, DMF, THF, DMSO, dioxane, etc. are used. Thereaction is carried out at 0° to 100° C. and is finished in 10 minutesto one day.

The products obtained in the above-mentioned steps may be isolated andpurified by conventional purification methods which are generally usedin the field of organic synthetic chemistry, for example, by filtration,extraction, washing, drying, concentration, recrystallization, variouschromatographic methods.

Specific examples of Compound (I) are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Compound                                                                             Structural Formula                                                     __________________________________________________________________________    Compound 1                                                                            ##STR6##                                                              Compound 2                                                                            ##STR7##                                                              Compound 3                                                                            ##STR8##                                                              Compound 4                                                                            ##STR9##                                                              Compound 5                                                                            ##STR10##                                                             Compound 6                                                                            ##STR11##                                                             __________________________________________________________________________

Compound (I) has an excellent skin-moisturizing activity and is used incosmetics of various forms, for example, skin-care products such aslotion, emulsion, cream, soap and pack; make-up products such aslipstick, foundation, eye shadow, eye liner; and hair-care products suchas shampoo and rinse.

Cosmetics of the present invention may be produced by blending by aconventional method Compound (I) and various components which aregenerally used for producing cosmetics, such as fats and oils,hydrocarbons, waxes, fatty acids, synthetic esters, alcohols,surfactants, thickeners, moisturizers, preservatives, fragrances,pigments, pharmaceutical chemicals and purified water, by a conventionalmethods.

In order to improve the spreadability of the cosmetics on the skin, theadhesiveness thereof to the skin and the water-repelling propertythereof on the skin, it is recommended to use pigments coated withCompound (I).

The content of Compound (I) in cosmetics may be from 0.001 to 10.0 w/w%, preferably from 0.005 to 5.0 w/w %, of the total weight of thecosmetics. ("%" is herein w/w %.)

Examples of fats and oils include jojoba oil, castor oil, olive oil,soybean oil, coconut oil, palm oil, cacao butter, mink oil, turtle oiland coconut oil fatty acid diethanolamides.

Examples of hydrocarbons include liquid paraffin, vaseline,microcrystalline wax and squalane.

Examples of waxes include beeswax, lanolin, carnauba wax and candelillawax.

Examples of fatty acids include myristic acid, palmitic acid, stearicacid, oleic acid and isostearic acid.

Examples of synthetic esters include isopropyl myristate, isopropylpalmitate, butyl oleate, myristyl myristate, octyldecyl myristate,propylene glycol monostearate, myristyllactate, isostearyl malate,glycerine monostearate and distearyldimethyl ammonium chloride.

Fats and oils, hydrocarbons, waxes, fatty acids and synthetic esters arecontained in the cosmetics in an amount of 0 to 30%.

Examples of alcohols include ethanol, 1,3-butylene glycol, propyleneglycol, lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol.Alcohols are contained in the cosmetics in an amount of 0 to 25%.

Examples of surfactants include polyoxyethylene-hardened castor oil,sodium lauryl sulfate, polyoxyethylene-glyceryl pyroglutamateisostearate, sodium alkylbenzene sulfonates, polyoxyethylene(10) stearylether, dialkyl sulfosuccinates, cetylpyridinium bromide, n-octadecyltrimethylammonium chloride, monoalkyl phosphates, N-acylglutamic acids,sucrose fatty acid esters, polyoxyethylene(20) sorbitan monostearate,sodium polyoxyethylene lauryl ether sulfate and polyoxyethylene-reducedlanolin.

The surfactants are usually employed in the cosmetics in an amount of0.1 to 5% and in the case of a shampoo, in an amount of 0.1 to 40%.

Examples of thickeners include carboxyvinyl polymers,methylpolysiloxanes, dextran, carboxymethyl cellulose, carrageenan,hydroxypropylmethyl cellulose. Thickeners are contained in the cosmeticsin an amount of 0 to 0.5%.

Examples of moisturizers include glycerin, propylene glycol,1,3-butylene glycol, pyrrolidonecarboxylic acid, lactic acid andhyaluronic acid. Moisturizers are contained in the cosmetics in anamount of 0 to 25%.

Examples of antiseptics include benzoic acid, salicylic acid,dehydroacetic acid, their salts, phenols such as parahydroxybenzoates,triclosan, halocarban. Preservatives are contained in the cosmetics inan amount of 0 to 0.3%.

Any fragrances which are conventionally used in cosmetics may be used.

Examples of pigments include iron oxide, titanium dioxide, zinc oxide,kaolin and talc. Pigments are contained in the cosmetics in an amount of0 to 1%. Pigments coated with Compound (I) maybe produced by uniformlydispersing pigments and Compound (I) dissolved in an alcohol such asethyl alcohol, removing the solvent by distillation to obtain dry coatedpigments and grinding them.

Examples of pharmaceutical chemicals include wheat germ oil, vitamin E,vitamin A, vitamin B₂, magnesium L-ascorbyl 2-phosphate, D-pantothenylalcohol, dipotassium glycyrrhetinate and glutathione. Pharmaceuticalchemicals are contained in the cosmetics in an amount of 0 to 5%.

Since Compound (I) have an excellent hair growth-stimulative effect asshown in Test Examples mentioned hereinafter, it may be used as hairgrowth stimulating tonic, hair growth stimulating lotion, hair growthstimulating cream, etc.

The hair growth stimulants of the present invention may be produced byblending Compound (I) and various components which are conventionallyused in producing hair growth stimulants, such as alcohols, fats andoils, fragrances, surfactants, microbicides, antioxidants, vitamins,antiinflammatory agents, refreshing agents, herb extracts and purifiedwater by a conventional methods.

The content of Compound (I) in hair growth stimulants may be from 0.01to 30%, preferably from 0.1 to 10%, of the total weight of the hairgrowth stimulants.

Examples of alcohols include ethanol, glycerin, 1,3-butylene glycol andpropylene glycol.

Examples of fats and oils include wheat germ oil, camellia oil, jojobaoil, olive oil, squalane, safflower oil, macadamia nut oil, avocado oiland soybean hydrogenated lecithin.

Any fragrances which are conventionally used in hair growth stimulantsmay be used.

Examples of surfactants include polyoxyethylene(60) hardened castor oil,polyoxyethylene(8) oleyl ether, polyoxyethylene(10) monooleate,polyoxyethylene(30) glyceryl monostearate, sorbitan monostearate,polyoxyethylene(20) sorbitan monooleate, sucrose fatty acid esters,hexaglyceryl monolaurate and polyoxyethylene-reduced lanolin.

Examples of microbicides include hinokitiol, triclosan,chlorohexidylgluconic acid salts, phenoxyethanol, resorcinol,isopropylmethylphenol, azulene, salicylic acid, light-sensitive elementsand zinc pyrithione.

Examples of antioxidants include butylhydroxyanisole,butylhydroxytoluene, gallic acid, propyl gallate and erysorbic acid.

Examples of vitamins include dl-α-tocopherol acetate, dl-α-tocopherol,vitamin E, benzyl nicotinate, D-pantothenyl alcohol, pantothenyl ethylether, biotin, pyridoxine hydrochloride and riboflavin.

Examples of anti-inflammatory agents include dipotassium glycyrrhetinateand allantoin.

Examples of refreshing agents include capcicum tincture and 1-menthol.

Examples of herb extracts include Swertia Japonica Makino extract,garlic extract, ginseng extract and aloe extract.

Solubilities of Compounds (I) and NAG in various oily bases are shownbelow.

0.2 g of one of Compound (I) (Compounds 1 to 4) or NAG and 19.8 g of theoily base shown in Table 2 were put in a beaker and stirred underheating. The temperature at which Compound (I) or NAG was completelydissolved in the oily base was measured. The results are shown in Table2.

                  TABLE 2                                                         ______________________________________                                                  Compound                                                                        Com-    Com-    Com-  Com-                                                    pound   pound   pound pound                                       Oily Base   1       2       3     4     NAG                                   ______________________________________                                        Liquid Paraffin                                                                           125     85      >175  115   Insoluble                             Squalane    130     110     >180  120   Insoluble                             Jojoba oil  >150    80      160   105   Insoluble                             Isopropyl Myristate                                                                       130     40      160   105   Insoluble                             Castor Oil  110     40      160   105   Insoluble                             Propylene Glycol                                                                          90      RT      105   85    Insoluble                             Ethanol     40      RT      60    40    Insoluble                             ______________________________________                                         RT: Room Temperature (°C.)                                        

As is apparent from Table 2, Compound (I) is more soluble in variousoily bases than NAG.

Next, sensory tests (moistness of skin, etc.) of cosmetics containingCompound. (I) and hair growth-stimulative effect of Compound (I) will beexplained below.

TEST EXAMPLE 1 Sensory Test of Lotion

The lotions obtained in Example 7 and Comparative Example 1 wereseparately applied to the face of 25 professional panelists, twice (inthe morning and the evening) a day, continuously for one month.

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                   Lotion                                                                                   Comparative                                                        Example 7  Example 1                                               Total Evaluation                                                                           ⊚                                                                     ◯                                                                        Δ                                                                            ⊚                                                                    ◯                                                                       Δ                           ______________________________________                                        (a) Smoothness of skin                                                                     22     2      1    2     9     14                                (b) Moistness of skin                                                                      14     8      3    15    7      3                                (c) Recovery of                                                                            20     2      3    2     10    13                                  roughening skin                                                             ______________________________________                                         ⊚: Very good. ◯: Good. Δ: ordinary.     

As is apparent from Table 3, the lotion of Example 7 (containingCompound 4) was much better than the lotion of Comparative Example 1(containing NAG) with respect to the smoothness of skin and the recoveryof roughening skin. With respect to the moistness of skin, the lotion ofExample was comparable to the lotion of Comparative Example 1.

TEST EXAMPLE 2 Sensory Test of Milky Lotion

The same sensory test as in Test Example 1 was carried out except thatmilky lotions obtained in Example 8 and Comparative Example 2 were usedin place of the lotions.

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                     Milky Lotion                                                                             Comparative                                                        Example 8  Example 2                                             Total Evaluation                                                                             ⊚                                                                     ◯                                                                        Δ                                                                            ⊚                                                                   ◯                                                                      Δ                           ______________________________________                                        (a) Smoothness of skin                                                                       22     2      1    2    7    16                                (b) Moistness of skin                                                                        15     8      2    4    4    17                                (c) Softness of skin                                                                         14     8      3    2    6    17                                (d) Recovery of                                                                              20     2      3    2    5    18                                  roughening skin                                                             ______________________________________                                    

TEST EXAMPLE 3 Sensory Test of Sunscreen Milky Lotion

The same sensory test as in Test Example 1 was carried out except thatthe sunscreen milky lotions obtained in Examples 11 and 12 were used inplace of the lotions.

The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                     Sunscreen Milky Lotion                                                        Example 12                                                                              Example 11                                             Total Evaluation                                                                             ⊚                                                                    ◯                                                                         Δ                                                                           ⊚                                                                    ◯                                                                     Δ                            ______________________________________                                        (a) Spread on skin                                                                           13    10      2   8     12  5                                  (b) Adhesion to skin                                                                         20     4      1   5     12  8                                  (c) Water-repellent                                                                          12    10      3   8     11  6                                    ability                                                                     ______________________________________                                    

TEST EXAMPLE 4 Hair Growth-Stimulative Effect

Hair on the back of male C3H/HeSlc-strain mice aged 9 weeks, which wasin the telogen of hair cycle, was clipped off by an electrichair-clipper. As the test compound, N-acetylglutamine-isostearyl(Compound 2) obtained in Example 2 was used. The test compound wasdissolved in a mixed solvent (ethanol:glycerine:1,3-butyleneglycol:purified water=6:0.5:0.5:3, v/v) to prepare a 0.5% test solution.The test solution was uniformly applied to the hair removed area of eachmouse of the test group once a day in an amount of 150 μl. The mixedsolvent was also applied to each mouse of the control group. Hairgrowth-stimulative effect was estimated by scoring the hair growing areaof the test compound treated group or of the control group and bymeasuring the mean value of the scored data in each group.

Regarding the mice of the test compound treated-group, the skin becameblack, indicating the formation of hair roots therein on the 10th day,and thereafter hair grew rapidly on the skin. On the 17th day, the hairgrowth-stimulative effect of the test compound was noticeable in themice of the test compound treated group. On the other hand, the hairgrowing area of the mice of the control group was very small even on17th day.

The results are shown in Table 6.

On about the 20th day, hairs grew almost completely in the hair removedarea of the mice of the test compound treated group, and anything wrongsuch as inflammation was not found in the test compound applied area.

                  TABLE 6                                                         ______________________________________                                        Test Solution  Sum of Scores*                                                 ______________________________________                                        Control Group   6                                                             Test Group     12                                                             ______________________________________                                         *: Sum of scores of five mice in each group.                                  Score:                                                                        0: No hairs grew.                                                             1: A few hairs grew.                                                          2: Some hairs grew to a middle degree.                                        3: Hairs grew all over the clipped area.                                 

BEST MODE FOR CARRYING OUT THE INVENTION

Examples and Comparative Examples are mentioned hereunder.

EXAMPLE 1 N-acetylglutamine-tocopheryl (Compound 1)

In 1200 ml of dried THF were dissolved 30 g (107 mmol) ofN-benzyloxycarbonyl-L-glutamine (hereinafter referred to asZ-L-glutamine), 46 g (107 mmol) of tocopherol and 1 g of4-dimethylaminopyridine, and cooled to 0° C. Then, 44.1 g (214 mmol) ofdicyclohexylcarbodiimide (DCC) was added thereto and allowed to stand at0° C. for 3 hours. The reaction mixture was allowed to stand in a coldroom at 3° C. for further 15 hours. Dicyclohexylurea (DCU) precipitatedwas removed, and the reaction mixture was again allowed to be cooled at3° C. DCU precipitated was removed, and the reaction mixture wasconcentrated under reduced pressure to obtain a gel-like substance, andthen 500 ml of hexane were added to the obtained gel-like substance. Themixture was triturated and then subjected to centrifugation to removehexane therefrom. The obtained precipitate was washed three times withhexane and then dried under reduced pressure to obtain a residue. Theresidue was dissolved in 500 ml of chloroform and then subjected tosilica gel column chromatography (chloroform:acetone=4:1, v/v) . Themain fraction of the eluate was concentrated and again subjected tosilica gel column chromatography (chloroform:methanol=9:1, v/v). Themain fraction of the eluate was concentrated under reduced pressure toobtain 40.8 g of a white powder. The obtained white powder was dissolvedin a mixed solvent of 700 ml of THF and 480 ml of acetic anhydride, and10 g of 10% Pd-C (50% H₂ O) were added thereto, and aerated withhydrogen gas for 7 hours. The solution was filtered, and the filtratewas dried under reduced pressure to obtain a residue. The residue wasdissolved in chloroform and. subjected to silica gel columnchromatography (chloroform:methanol=9:1, v/v). The main fraction of theeluate was concentrated under reduced pressure to obtain 28 g ofCompound 1 as a white powder.

Appearance: colorless powder

Melting Point: 144.0°-145.2 ° C.

Specific Rotatory Power: [α]_(D) ²³ =-30.9° (C 1.16, CH₃ OH)

Ultraviolet Absorption Spectrum (CH₃ OH solution): λ max nm (ε) 225.0(shoulder, 11,000), 277.1 (1,900), 283.5 (2,000)

Infrared Absorption Spectrum (KBr tablet): ν max cm⁻¹ 3415, 3332, 3210,2925, 2868, 1741, 1666, 1641, 1545, 1462, 1209, 1167

FAB-MS Spectrum (matrix: m-nitrobenzyl alcohol): m/z 601 (M+I)

HR-FAB-MS: C₃₆ H₆₁ N₂ O₅ Measured: 601.4590 Calculated: 601.4581

¹ H NMR Spectrum (400 MHz, CDCl₃ solution): δ ppm (integral,multiplicity) 0.84 (3H, d), 0.85 (3H, d), 0.87 (6H, d), 1.00-1.62 (22H,m), 1.65-1.90 (4H, m), 1.96 (3H, s), 1.99 (3H, m), 2.05 (3H, m), 2.08(3H, m) , 2.10-2.30 (1H, m) , 2.30-2.54 (3H, m), 2.57 (2H, t), 4.87 (1H,m), 5.58 (1H, brs), 6.19 (1H, brs), 6.78 (1H, brs)

¹³ C NMR Spectrum (100 MHz, CDCl₃ solution): δ ppm 11.82, 12.14, 12.99,19.60, 19.63, 19.66, 19.70, 19.76, 20.16, 21.05, 22.63, 22.72, 23.09,24.45, 24.81, 27.99, 28.16, 31.04, 32.07, 32.71, 32.79, 37.31, 37.37,37.41, 37.48, 37.58, 39.43, 52.27, 75.20, 117.59, 123.24, 124.81,126.44, 140.16, 149.71, 170.80, 170.83, 174.60

Elementary Analysis: C₃₆ H₆₀ N₂ O₅ Measured: C 71.68 H 10.33 N 4.43Calculated: C 71.96 H 10.07 N 4.66

EXAMPLE 2 N-acetylglutamine-isostearyl (Compound 2)

In 700 ml of dried THF were dissolved 20 g (71.36 mmol) ofZ-L-glutamine, 17.7 g (65.4 mmol) of isostearyl alcohol and 580 mg of4-dimethylaminopyridine and cooled to 0° C. Then, 14.7 g (71.24 mmol) ofDCC was added thereto and allowed to stand at 0° C. for 3 hours. Thereaction mixture was allowed to stand in a cold room at 3° C. forfurther 15 hours. DCU precipitated was removed, and the reaction mixturewas again allowed to be cooled at 3° C. DCU precipitated was removed,and the reaction mixture was concentrated under reduced pressure andsubjected to silica gel column chromatography (hexane:methanol=8:2,v/v). The main fraction of the eluate was concentrated to obtain 22.5 gof a caramel-like substance.

The substance was dissolved in a mixed solvent of 300 ml of THF and 40ml of acetic anhydride. 3.5 g of 10% Pd-C (50% H₂ O) was added thereto,and aerated with hydrogen gas for 7 hours. The solution was filtered,and the filtrate was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography (ethyl acetate:ethanol=8:2, v/v) . The main fraction of the eluate was concentratedunder reduced pressure to obtain a caramel-like substance.

The caramel-like substance was dissolved in 100 ml of ethyl acetate,washed three times with 50 ml of 1% sodium bicarbonate and then oncewith 100 ml of water, dehydrated with magnesium sulfate and thenconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography (ethyl acetate: ethanol=8:2, v/v) . The mainfraction was concentrated to obtain 13.5 g of Compound 2 as whitecrystals.

Appearance: colorless powder

Melting Point: 67.0°-68.0° C.

Specific Rotatory Power: [α]_(D) ²³ =-18.2° (C 1.33, CH₃ OH)

Ultraviolet Absorption Spectrum (CH₃ OH solution): λ max nm (ε) terminalabsorption only

Infrared Absorption Spectrum (KBr tablet): ν max cm⁻¹ 3415, 3288, 2954,1743, 1655, 1552, 1636, 1302, 1244, 1176

FAB-MS Spectrum (matrix: m-nitrobenzyl alcohol): m/z 441 (M+1)

HR-FAB-MS: C₂₅ H₄₉ N₂ O₄ Measured: 441.3 685 Calculated: 441.3692

¹ H NMR Spectrum (400 MHz, CDCl₃ solution): δ ppm (integral,multiplicity) 0.70-1.00(24H, m), 1.00-1.60(10H, m), 1.60-1.80(10H, m),1.85-2.05 (1H, m), 2.03 (3H, s), 2.10-2.40 (3H, m), 4.07(2H, m),4.62(1H, m), 5.61(1H, brs), 6.19(1H, brs), 6.57 (1H, m)

³ C NMR Spectrum (100 MHz, CDCl₃ solution): δ ppm 18.40, 18.47, 18.54,18.62, 18.69, 22.53, 22.64, 22.71, 23.15, 24.93, 25.01, 26.43, 26.52,28.43, 29.32, 29.42, 29.53, 29.60, 29.63, 29.72, 29.88, 29.91, 29.95,30.04, 30.08, 30.10, 31.07, 31.20, 31.93, 37.60, 37.63, 37.72, 37.75,37.91, 37.99, 44.53, 44.59, 44.62, 48.26, 48.34, 48.44, 48.48, 48.61,48.66, 51.17, 51.30, 51.40, 52.09, 67.08, 67.13, 67.16, 67.38, 67.42,170.49, 172.12, 172.16, 174.49

Elementary Analysis: C₂₅ H₄₈ N₂ O₄ Measured: C 67.79 H 11.23 N 6.15Calculated: C 68.14 H 10.98 N 6.36

EXAMPLE 3 N-acetylglutamine-cholesteryl (Compound 3)

In 600 ml of dried THF were dissolved 14.06 g (50.17 mmol) ofZ-L-glutamine, 19.4 g (50.17 mmol) of cholesterol and 380 mg of4-dimethylaminopyridine and cooled to 0° C. Then, 10.22 g (49.5 mmol) ofDCC was added thereto and allowed to stand at 0° C. for 3 hours. Thereaction mixture was then allowed to stand in a cold room at 3° C. forfurther 15 hours. DCU precipitated was removed, and the reaction mixturewas again allowed to be cooled at 3° C. DCU precipitated was removed,and the reaction mixture was concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography (hexane:ethylacetate=7:3, v/v). The main fraction of the eluate was concentrated toobtain 20.3 g of a white powder. This operation was repeated three timesand 44.9 g of the substance obtained was dissolved in a mixed solvent of1000 ml of THF and 32.6 ml of acetic anhydride. 6 g of 10% Pd-C (50% H₂O) was added thereto, and aerated with hydrogen gas for 6 hours. Thesolution was filtered, and the filtrate was concentrated under reducedpressure. The residue was subjected to silica gel column chromatography(chloroform:ethanol=8:2, v/v). The main fraction of the eluate wasconcentrated under reduced pressure to obtain 20.7 g of Compound 3 as awhite powder.

Appearance: colorless powder

Melting Point: 182.0°-184.0° C.

Specific Rotatory Power: [α]_(D) ²³ =-32.5° (c 0.44, CH₃ OH)

Ultraviolet Absorption Spectrum (CH₃ OH solution): λ max nm (ε) terminalabsorption only

Infrared Absorption Spectrum (KBr tablet): ν max cm⁻¹ 3423, 3298, 2935,1739, 1664, 1541, 1375, 1207, 1136, 1007

FAB-MS Spectrum (matrix: m-nitrobenzyl alcohol): m/z 557 (M+H)

HR-FAB-MS: C₃₄ H₅₇ N₂ O₄ Measured: 557. 4136 Calculated: 557. 4319

¹ H NMR Spectrum (400 MHz, CDCl₃ solution): δ ppm (integral,multiplicity) 0.68 (3H, s), 0.86 (3H, d), 0.87 (3H, d), 0.92 (3H, d),1.02 (3H, s), 0.85-1.02 (3H, m), 1.02-1.70 (17H, m), 1.78-2.03(7H, m),2.03(3H, s), 2.15-2.23(1H, m), 2.26-2.40 (4H, m), 4.55 (1H, m), 4.67(1H, m), 5.37 (1H, brd), 5.58(1H, brs), 6.36(1H, brs), 6.58(1H, d)

¹³ C NMR Spectrum (100 MHz, CDCl₃ solution): δ ppm 11.87, 18.74, 19.30,21.05, 22.57, 22.82, 23.18, 23.86, 24.30, 27.68, 28.02, 28.24, 28.80,31.36, 31.93, 32.00, 35.80, 36.22, 36.92, 37.95, 39.54, 39.75, 42.35,50.05, 52.07, 56.20, 56.73, 75.70, 123.07, 139.24, 170.66, 171.47,174.63

Elementary Analysis: C₃₄ H₅₆ N₂ O₄ Measured: C 72.96 H 10.46 N 4.99Calculated: C 73.34 H 10.14 N 5.03

EXAMPLE 4 N-acetylglutamine-stearyl (Compound 4)

In 186 ml of DMF was dissolved 9.3 g (0.0495 tool) ofN-acetyl-L-glutamine, 2.18 g (0.0545 mol) of 60% sodium hydride wasadded thereto, and stirred for 30 minutes at 10° C. Then, 20.7 g (0.0545tool) of stearyl iodide was added thereto and reacted at 60° C. for 5hours. After the reaction was completed, the reaction mixture was pouredinto 2 liter of water. The crystals precipitated were dissolved in 1liter of ethyl acetate under heating, dried with magnesium sulfate andthen concentrated under reduced pressure. The residue was cooled, andthe crystals precipitated were taken out by filtration. The obtainedcrystals were subjected to silica gel column chromatography(chloroform:methanol=10:1, v/v) to obtain 13 g of Compound 4 as whitecrystals.

Appearance: colorless powder

Melting Point: 118.0°119.0° C.

Specific Rotatory Power: [α]_(D) ²³ =+6.7° (C 1.06, CHCl₃)

Ultraviolet Absorption Spectrum (CH₃ OH solution): λ max nm (ε) terminalabsorption only

Infrared Absorption Spectrum (KBr tablet): ν max cm⁻¹ 3419, 3332, 3209,2916, 2848, 1732, 1664, 1635, 1549, 1471, 1415, 1311, 1223, 1176, 719

FAB-MS Spectrum (matrix: m-nitrobenzyl alcohol): m/z 441 (M+H)

HR-FAB-MS: C₂₅ H₄₉ N₂ O₄ Measured: 441.3710 Calculated: 441. 3692 p0 ¹ HNMR Spectrum (400 MHz, CDCl₃ solution): δ ppm (integral, multiplicity)0.88 (3H, d), 1.20-1.70 (32H, m), 1.80-2.00 (1H, m), 2.04(3H, s),2.05-2.40(3H, m), 4.14(2H, t), 4.59(1H, m), 5.37(1H, brs), 6.21(1H,brs), 6.45(1H, d)

¹³ C NMR Spectrum (100 MHz, CDCl₃ solution): δ ppm 14.15, 22.73, 23.24,25.84, 28.55, 28.77, 29.24, 29.40, 29.53, 29.63, 29.70, 29.74, 31.97,32.00, 52.03, 66.05, 170.62, 172.08, 174.43

Elementary Analysis: C₂₅ H₄₈ N₂ O₄ Measured: C 67.87 H 11.29 N 6.16Calculated: C 68.14 H 10.98 N 6.36

EXAMPLE 5 O-(N-acetyl-L-glutaminyl)hydroquinone (Compound 5)

In 700 ml of THF were dissolved 14 g (49.95 mmol) of N-Z-L-glutamine, 10g (49.94 mmol) of monobenzylhydroquinone and 0.4 g of4-dimethylaminopyridine and cooled to 0° C. Then, 10.3 g (49.92 mmol) ofDCC was added thereto and stirred at 0° C. for 20 hours. DCUprecipitated was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in 1.2liter of THF, 3.66 ml (38.8 mmol) of acetic anhydride and 3.5 g of 10 %Pd-C catalyst (50% H₂ O) were added thereto, and aerated with hydrogengas for 5 hours. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography (chloroform:methanol=9: 1,v/v), and the main fraction of the eluate was concentrated under reducedpressure to obtain 7.9 g of Compound 5.

Appearance: colorless powder

Melting Point: 139.0°-141.0° C.

Specific Rotatory Power: [α]_(D) ²³ =-47.4° (C 1.00, CH₃ OH)

Ultraviolet Absorption Spectrum (CH₃ OH solution): λ0 max nm (ε) 211.0(shoulder, 4,900), 222.0 (5,900), 277.0 (1,900)

Infrared Absorption Spectrum (KBr tablet): ν max cm⁻¹ 3481, 3359, 3336,3197, 1751, 1672, 1649, 1610, 1601, 1525, 1512, 1207, 1190, 1122, 1097

FAB-MS Spectrum (matrix: m-nitrobenzyl alcohol): m/z 281 (M+H)

HR-FAB-MS: C₁₃ H₁₇ N₂ O₅ Measured: 281. 1137 Calculated: 281. 1138

¹ H NMR Spectrum (400 MHz, CD₃ OD solution): δ ppm (integral,multiplicity) 2.01(3H, s), 2.03-2.12(1H, m), 2.24-2.32(1H, m), 2.39(2H,t), 4.55(1H, dd), 6.76(2H, d), 6.91(2H, d)

¹³ C NMR Spectrum (100 MHz, CD3OD solution): δ ppm 22.30, 28.10, 32.47,53.75, 116.68, 123.19, 144.63, 156.53, 172.54, 173.61, 177.36

Elementary Analysis: C₁₃ H₁₆ N₂ O₅ Measured: C 55.53 H 5.71 N 9.88Calculated: C 55.71 H 5.75 N 10.00

EXAMPLE 6 O,O-bis(N-acetyl-L-glutaminyl)hydroquinone (Compound 6)

In 1.5 liter of dried THF were dissolved 16.8 g (59.94 mmol) ofN-Z-L-glutamine, 3.3 g (29.97 mmol) of hydroquinone and 0.45 g of4-dimethylaminopyridine, cooled to 0° C., and 12.6 g (61.07 mmol) of DCCwas added thereto and stirred at 0° C. for 20 hours. DCU precipitatedwas removed by filtration, and the filtrate was concentrated underreduced pressure. The residue was dissolved in 1.7 liter of acetic acid,50 ml of acetic anhydride and 6 g of 10% Pd-C catalyst (50% H₂ O) wereadded thereto, and aerated with hydrogen gas for 6 hours. The catalystwas removed by filtration, and the filtrate was concentrated underreduced pressure. The residue was triturated three times with 100 ml ofTHF and then once with 100 ml of methanol to obtain 5.3 g of Compound 6.

Appearance: colorless powder

Melting Point: 196.0°-197.0° C.

Specific Rotatory Power: [α]_(D) ²³ =-45.7° (c 0.53, DMSO)

Ultraviolet Absorption Spectrum (CH₃ OH solution): λ0 max nm (ε) 217.0(7,500), 262.0 (500), 267 (shoulder, 400)

Infrared Absorption Spectrum (KBr tablet): ν max cm⁻¹ 3423, 3372, 3203,2951, 1751, 1660, 1540, 1502, 1419, 1313, 1211, 1182, 1159, 1018, 976,575, 515

FAB-MS Spectrum (matrix: m-nitrobenzyl alcohol): m/z 451 (M+H)

HR-FAB-MS: C₂₀ H₂₈ N₄ O₈ Measured: 451. 1840 Calculated: 451. 1829

¹ H NMR Spectrum (400 MHz, DMSO-d₆ solution): δ ppm (integral,multiplicity) 1.90(6H, s), 1.90-1.99(2H, m), 2.05-2.14(2H, m), 2.25(4H,t), 4.38(2H, m), 6.81 (2H, brs), 7.16(4H, s), 7.34 (2H, brs), 8.46 (2H,d)

¹³ C NMR Spectrum (100 MHz, DMSO-d₆ solution): δ ppm 22.16, 26.27,31.00, 52.10, 122.64, 147.87, 169.89, 171.03, 173.27

Elementary Analysis: C₂₀ H₂₆ N₄ O₈ Measured: C 52.97 H 5.87 N 12.03Calculated: C 53.33 H 5.82 N 12.44

EXAMPLE 7 Lotion

                  TABLE 7                                                         ______________________________________                                        Ingredient              Amount (%)                                            ______________________________________                                        a. 1,3-Butylene Glycol  10.0                                                  b. Ethanol              5.0                                                   c. Methyl Parahydroxybenzoate                                                                         0.1                                                   d. N-acetylglutamine-stearyl (Compound 4)                                                             0.1                                                   e. Wheat Germ Oil       0.1                                                   f. Polyoxyethylene-glyceryl Pyroglutamate                                                             1.0                                                    Isostearate (25 E.O.)                                                        g. Fragrance            0.05                                                  h. Purified water       83.65                                                 ______________________________________                                    

To a homogeneous solution of ingredients (a) and (h) shown in Table 7was added a homogeneous solution of ingredients (b), (c), (d), (e), (f)and (g), and the mixture was stirred to obtain a lotion.

COMPARATIVE EXAMPLE 1 Lotion

A lotion was prepared in the same manner as in Example 7 except that NAGwas used in place of ingredient (d) (Compound 4).

EXAMPLE 8 Milky Lotion

                  TABLE 8                                                         ______________________________________                                        Ingredient              Amount (%)                                            ______________________________________                                        a. Wheat Germ Oil       3.0                                                   b. Squalane             4.0                                                   c. N-acetylglutamine-stearyl (Compound 4)                                                             0.1                                                   d. Sorbitan Monostearate                                                                              1.5                                                   e. Polyoxyethylene-Sorbitan Monostearate                                                              1.5                                                    (20 E.O.)                                                                    f. 1,3-Butylene Glycol  15                                                    g. Triethanolamine      0.3                                                   h. Methyl Parahydroxybenzoate                                                                         0.1                                                   i. Carboxyvinyl Polymer 0.1                                                   j. Fragrance            0.05                                                  k. Purified Water       74.35                                                 ______________________________________                                    

Ingredients (a), (b), (c), (d), (e) and (f) shown in Table 8 were meltedunder heating. An aqueous solution prepared by dissolving ingredients(g) and (h) in a half amount of ingredient (k) under heating was addedthereto, and mixed by stirring. A mixture comprising ingredient (i) andthe remaining half amount of ingredient (k) was added thereto along withingredient (j) and mixed by stirring. Then the mixture was cooled toroom temperature to obtain a milky lotion.

COMPARATIVE EXAMPLE 2 Milky lotion

A milky lotion was prepared in the same manner as in Example 8 using theingredients shown in Table 8 except for ingredient (c) (Compound 4).

EXAMPLE 9 Cream

                  TABLE 9                                                         ______________________________________                                        Ingredient          Amount (%)                                                ______________________________________                                        a. Squalane         5.0                                                       b. Isopropyl Myristate                                                                            3.0                                                       c. Wheat Germ Oil   3.0                                                       d. Bees Wax         5.0                                                       e. Cetanol          2.0                                                       f. Stearic Acid     4.0                                                       g. Gricerine Monostearate                                                                         3.0                                                       h. N-acetylglutamine-stearyl                                                                      0.5                                                         (Compound 4)                                                                i. Triethanolamine  0.4                                                       j. Methyl Parahydroxybenzoate                                                                     0.1                                                       k. 1,3-Butylene Glycol                                                                            5.0                                                       l. Fragrance        0.05                                                      m. Purified Water   68.95                                                     ______________________________________                                    

Ingredients (a), (b), (c), (d), (e), (f), (g) and (h) shown in Table 9were melted under heating. An aqueous solution prepared by dissolvingingredients (i), (j), (k), (l) and (m) under heating was added thereto,and mixed by stirring. The mixture was cooled to room temperature toobtain a cream.

EXAMPLE 10 Face Wash

                  TABLE 10                                                        ______________________________________                                        Ingredient           Amount (%)                                               ______________________________________                                        a. Myristic Acid     25.0                                                     b. Stearic Acid      6.0                                                      c. Stearic Acid Diethanolamide                                                                     4.0                                                      d. Ethylene Glycol Monostearate                                                                    1.0                                                      e. N-acetylglutamine-stearyl                                                                       0.1                                                        (Compound 4)                                                                f. Methyl Parahydroxybenzoate                                                                      0.1                                                      g. Potassium Hydroxide                                                                             6.0                                                      h. 1,3-Butylene Glycol                                                                             10.0                                                     i. White Sugar       4.0                                                      j. Fragrance         0.05                                                     k. Purified Water    43.75                                                    ______________________________________                                    

Ingredients (a), (b), (c), (d) and (e) shown in Table were melted underheating. An aqueous solution prepared by dissolving ingredients (f),(g), (h), (i) and (k) under heating was added thereto, and mixed bystirring. Then, ingredient (j) was added thereto and mixed by stirring.The mixture was cooled to room temperature to obtain a face wash.

EXAMPLE 11 Sunscreen Milky Lotion

                  TABLE 11                                                        ______________________________________                                        Ingredient              Amount (%)                                            ______________________________________                                        a. Propylene Glycol     4.0                                                   b. N-acetylglutamine-stearyl                                                                          0.6                                                     (Compound 4)                                                                c. Titanium Dioxide     3.0                                                   d. Stearic Acid         1.0                                                   e. Liquid Paraffin      1.0                                                   f. Polyoxyethylene-Sorbitan Monostearate                                                              1.5                                                     (20 E.O.)                                                                   g. Oleophilic Glycerine Stearate                                                                      1.0                                                   h. Triethanolamine      0.7                                                   i. Methyl Parahydroxybenzoate                                                                         0.2                                                   j. Carboxyvinyl Polymer 0.2                                                   k. Fragrance            0.05                                                  l. Purified Water       86.75                                                 ______________________________________                                    

Ingredients (a) and (b) shown in Table 11 were melted under heating, andingredient (c) was added thereto. The mixture was uniformly dispersedusing a three-roll mill to prepare a pigment part. Ingredients (d) and(e) were melted under heating. An aqueous solution prepared bydissolving ingredients (f), (g), (h), (i), (j), (l) and the pigment partunder heating was added thereto and mixed by stirring. Ingredient (k)was added thereto and mixed by stirring. The mixture was cooled to roomtemperature to obtain a sunscreen milky lotion.

EXAMPLE 12 Sunscreen Milky Lotion

A sunscreen milky lotion was prepared in the same manner as in Example11 except that ingredient (c) * coated with ingredient (b) was used inplace of ingredients (b) (Compound 4) and (c) (titanium dioxide).

* In 30 ml of ethyl alcohol was dissolved 0.2 g of Compound 4 underheating, then, 10 g of titanium dioxide were added thereto and uniformlydispersed. After the solvent was removed by distillation, the driedproduct was powdered to obtain a powder (having a mean particle size of0.05 microns) of titanium dioxide coated with Compound 4.

EXAMPLE 13 Hair Growth Stimulating Tonic

                  TABLE 12                                                        ______________________________________                                        Ingredient           Amount (%)                                               ______________________________________                                        a. N-acetylglutamine-isostearyl                                                                    2                                                          (Compound 2)                                                                b. Ethanol           55                                                       c. Propylene Glycol  5                                                        d. DL-α-tocopherol Acetate                                                                   0.1                                                      e. POE(60)-Hardened Castor Oil                                                                     0.5                                                      f. Fragrance         0.1                                                      g. Purified Water    37.3                                                     ______________________________________                                    

Ingredients (b) and (g) shown in Table 12 were uniformly mixed. A liquidmixture prepared by mixing ingredients (a), (c), (d), (e) and (f) underheating was added thereto and stirred uniformly to obtain a hair growthstimulating tonic.

We claim:
 1. An N-acylglutamine derivative of formula (I): ##STR12##wherein R¹ represents ##STR13## wherein R³ represents an alkyl having 1to 6 carbon atoms; and R² represents an alkyl having 1 to 6 carbonatoms.
 2. N-acetylglutamine-tocopheryl. 3.N-acetylglutamine-cholesteryl.
 4. O-(N-acetyl-L-glutaminyl)hydroquinone.
 5. O,O-bis (N-acetyl-L-glutaminyl) hydroquinone.
 6. Acomposition comprising an effective amount of N-acylglutamine derivativeof formula (I) as defined in claim 1 and a cosmetic component.
 7. Acomposition according to claim 6, further comprising a pigment.
 8. Acomposition comprising a hair growth stimulant and an effective amountof N-acylglutamine derivative of formula (I) as defined in claim 1.